Tramadol hydrochloride solution

ABSTRACT

Disclosed herein is an analgesic solution for the treatment of pain comprising a pain-relieving effective amount of tramadol or a pharmaceutically acceptable salt thereof, a method of treating pain by administering said analgesic solution to a subject in need thereof, a kit that includes containers of the analgesic solution, and a dosing regimen for the analgesic solution.

This application is a continuation of U.S. patent application Ser. No.17/009,565, filed Sep. 1, 2020, which claims the benefit of U.S. PatentApplication No. 62/932,963, filed Nov. 8, 2019, each of which is herebyincorporated by reference.

FIELD OF THE INVENTION

Disclosed herein is an oral analgesic solution for the treatment of paincomprising a pain-relieving effective amount of tramadol or apharmaceutically acceptable salt thereof, a method of treating pain byadministering said analgesic solution to a subject in need thereof, akit that includes containers of the analgesic solution, and a dosingregimen for the analgesic solution.

BACKGROUND

Tramadol hydrochloride is referred to chemically as (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol,hydrochloride. Tramadol is an opioid agonist and inhibitor ofnorepinephrine and serotonin re-uptake. Opioid activity is due to bothlow affinity binding of tramadol and higher affinity binding of atramadol metabolite (viz.,3-[cis-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-phenol orO-desmethyltramadol (ODMT)) to μ-opioid receptors. In animal models,ODMT is up to 6 times more potent than tramadol in producing analgesiaand 200 times more potent in μ-opioid binding. The relative contributionof both tramadol and ODMT to human analgesia is dependent upon theplasma concentrations of each compound.

Tramadol hydrochloride has been commercially available as immediaterelease tablets since 1995 under the brand name ULTRAM®. ULTRAM® tabletscontain 50 mg of tramadol hydrochloride, together with inactiveingredients including: pregelatinized corn starch, modified starch(corn), hypromellose, lactose, magnesium stearate, microcrystallinecellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate,titanium dioxide, and carnuba wax.

ULTRAM® is indicated in adults for the management of pain severe enoughto require an opioid analgesic and for which alternative treatments areinadequate. Studies have shown that ULTRAM® is useful for the treatmentof chronic pain in elderly patients associated with, for example,osteoarthritis and chronic low-back syndrome.

Some patients may experience dizziness, vertigo, nausea, and vomitingafter ingesting ULTRAM® tablets. Accordingly, for patients not requiringrapid onset of analgesic effect, the tolerability of ULTRAM® can beimproved by initiating therapy with a titration regimen. See, e.g.,Kamin et al., Analgesic Regimen, U.S. Pat. No. 6,339,105 B1 (“Kamin”);see also the Prescribing Information for ULTRAM® (tramadolhydrochloride) tablets, for oral use, as of Oct. 7, 2019 (“ULTRAM®Label”). For instance, the ULTRAM® Label recommends starting ULTRAM® at25 mg/day and titrated in 25 mg increments as separate doses every 3days to reach 100 mg/day (25 mg four times a day). Thereafter the totaldaily dose may be increased by 50 mg as tolerated every 3 days to reach200 mg/day (50 mg four times a day). After titration, ULTRAM® 50 to 100mg can be administered as needed for pain relief every 4 to 6 hours notto exceed 400 mg/day.

A problem associated with the use of ULTRAM® and the recommended dosetitration is the necessity to break scored tablets. And a furthercomplication is that generic equivalents of ULTRAM® are not scored.Having to break a scored/unscored tablet may be problematic in that anirregular break may result in incorrect dosing. This also may beproblematic insofar that tramadol hydrochloride has a bitter taste,thereby, resulting in patient non-compliance. And a separate problemthat is unrelated to the recommended dose titration is that ULTRAM® isprescribed typically to elderly patients (e.g., for the relief of painassociated with osteoarthritis). It is generally recognized that manyelderly people will encounter difficulties swallowing conventional oraldosage forms, including tablets. See, e.g., Chang et al.,Fast-Dissolving Tablets, Pharm. Tech. (2000) 24: 52-58 (“Chang”).Accordingly, ULTRAM® may be unsuitable for many elderly patients becausesaid patients may encounter problems swallowing a tablet.

Extemporaneous tramadol preparations are known. See, e.g., Wagner etal., Stability of oral liquid preparations of tramadol in strawberrysyrup and a sugar-free vehicle, Am. J. Health-Syst. Pharm. (2003)60(12): 1268-1270 (“Wagner”) and Polonini et al., Compatibility ofcholecalciferol, haloperidol, imipramine hydrochloride,levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacrolimusmonohydrate, terbinafine, tramadol hydrochloride and valsartan inSrySpend® PH4 oral suspensions, Pharmazie (2016) 71(4): 185-191(“Polonini”). Wagner describes preparing an oral suspension of tramadolhydrochloride by crushing ULTRAM® tablets and suspending the crushedpowder in one of two vehicles (viz., either ORA-SWEET® SF or ORA-PLUS®and strawberry syrup). Wagner states that the extemporaneous preparedsuspension should include a label stating “Shake Well Before Use,” andrecommends mixing the suspension with chocolate syrup beforeadministration to mask the bitter aftertaste. Polonini describespreparing an oral suspension by compounding tramadol hydrochloride usingSyrSpend® SF PH4 (pH 4.2). Based on data presented therein, Poloninistates that the beyond-use date of the preparation was found to be atleast 90 days both at refrigerated and at room temperature. It isgenerally recognized that extemporaneously prepared suspensions maysuffer numerous problems, including, for example, poor taste, inadequatecontent uniformity, limited shelf-life, the possibility of microbialcontamination, use of unapproved container/closure, poor taste, amongothers. And as related to an opioid agonist, such as tramadol,extemporaneously prepared suspensions may give rise to calculation andmeasurement errors may lead to an overdosed patient, which may lead toseizure and respiratory depression.

The analgesic solution disclosed and claimed herein is meant to overcomethe shortcomings of the ULTRAM® tablets for oral use, as well as knownextemporaneously prepared oral suspensions.

US 2018/0140566 describes acetaminophen and tramadol compound oralsolution in a solvent system comprising polyethylene glycol.

WO 2019/161938 describes an oral pharmaceutical solution comprisingtramadol or a pharmaceutically acceptable salt thereof in aconcentration of 10 mg/mL to 40 mg/mL. It was observed that more dilutesolutions, which required larger volumes to be administered, resulted ina longer lasting intense bitter aftertaste. WO 2019/161938 furtherteaches that the relatively high concentrations of taste masking agentsthat are necessary for masking the bitterness of tramadol hydrochlorideat a concentration below 10 mg/mL, such as 8 mg/ml, cause a negativeeffect on solubility, resulting in the formation of a suspension withthe presence of visible particles that become apparent upon production,and still exhibited a disagreeable sweet aftertaste.

Furthermore, more dilute drug solutions typically degrade faster thanmore concentrated solutions and require larger doses, which may be moredistasteful for less palatable drugs.

SUMMARY OF THE INVENTION

The present inventors have discovered that a low concentration solutionof tramadol hydrochloride (for example, at 5 mg/mL) can be preparedwhich is stable and does not exhibit the intense bitter aftertastecommon to tramadol solutions.

One aspect is an aqueous oral analgesic solution comprising:

-   -   (a) from about 4.5 to about 5.5 mg/mL (preferably about 5 mg/mL)        of tramadol hydrochloride as the sole active ingredient;    -   (b) from about 4 to about 10% w/v of propylene glycol;    -   (c) from about 10 to about 30% w/v of glycerin;    -   (d) a sufficient amount of a buffer to maintain the pH of the        oral solution from about 4.5 to about 5.5;    -   (e) from about 0.01% to about 0.2% sucralose;    -   (f) a flavoring agent in an amount of from about 0.1% w/v to        about 1% or 5% w/v;    -   (g) sodium benzoate in an amount of from about 0.1% w/v to about        1% w/v; and    -   (h) a sufficient amount of water.

In one embodiment, the amount of propylene glycol ranges from about 5 toabout 7% w/v. The buffer can be a citrate buffer, such as a mixture ofcitric acid and trisodium citrate. The citrate buffer can be present inan amount of from about 0.2% w/v to about 0.4% w/v. The sucralose can bepresent in an amount of about 0.1% w/v. The flavoring agent, which canbe grape flavor, can be present in an amount of from about 0.2% w/v toabout 0.4% w/v. The sodium benzoate can be present in an amount of fromabout 0.3% w/v to about 0.4% w/v.

Another aspect is an aqueous oral analgesic solution comprising:

-   -   (a) about 5 mg/mL of tramadol hydrochloride as the sole active        ingredient;    -   (b) about 5% w/v of propylene glycol;    -   (c) about 20% w/v of glycerin;    -   (d) about 0.1% w/v of citric acid and about 0.2% w/v of        trisodium citrate dihydrate;    -   (e) about 0.07% w/v of sucralose;    -   (f) a flavoring agent in an amount of from about 0.1% w/v to        about 1% w/v;    -   (g) about 0.375% w/v of sodium benzoate; and    -   (h) water,        wherein the solution has a pH of from about 4.5 to about 5.5.

In one embodiment of any of the oral solutions described herein, the pHof the oral solution ranges from about 4.8 to about 5.4. In anotherembodiment, the pH is 5.0 or 5.1.

In one embodiment of any of the oral solutions described herein, thesolution does not contain any active pharmaceutical ingredients otherthan tramadol hydrochloride.

In one embodiment of any of the oral solutions described herein, theoral solution is free or substantially free of (i) sugars (such assucrose), (ii) parabens (such as methylparaben or propylparaben), (iii)non-ionic surfactants and/or co-solvents (such as castor oil, modifiedcastor oil, ethanol, polyethylene glycol, povidone, copovidone, andsorbitan monolaurate), (iv) mint oil, (v) aniseed flavor, (vi) saccharinand salts thereof (such as sodium saccharin), (vii) sodium cyclamate,(viii) polyoxyl 40 hydrogenated castor oil, and (ix) any combination ofany of the foregoing.

Another aspect of the present invention is an oral analgesic solutionfor the treatment of pain comprising: (a) tramadol or a pharmaceuticallyacceptable salt thereof in an amount of from about 0.1% w/v to about2.5% w/v; (b) a non-aqueous solvent in an amount of from about 0 toabout 30% w/v; (c) a taste enhancer in an amount of from about 0% w/v to30% w/v; (d) a sufficient amount of a buffer to maintain the pH of theoral solution from about 3 to about 7; (e) a sweetener in an amount offrom about 0.01% w/v to about 1.0% w/v; (f) a flavoring agent in anamount of from about 0.1% w/v to about 5% w/v; (g) a preservative in anamount of from about 0% w/v to about 4% w/v; (h) optionally, a pHadjusting agent; and (i) a sufficient amount of water.

Yet another aspect is a method of treating pain in a patient in needthereof comprising administering an effective amount of an analgesicsolution as described herein.

Yet another aspect is a method of treating a patient (e.g., an adultpatient) having pain severe enough to require an opioid analgesic andfor which alternative treatments are inadequate. The method comprisesadministering an effective amount of an analgesic solution as describedherein.

In the methods described herein, for patients not requiring rapid onsetof analgesic effect, the tolerability of the analgesic solution can beimproved by initiating therapy with the following titration regimen:Start administering the analgesic solution in a sufficient amount toprovide 25 mg per day of tramadol or a pharmaceutically acceptable saltthereof (e.g., tramadol hydrochloride) and titrated in 25 mg incrementsas separate doses every 3 days to reach 100 mg per day (25 mg four timesa day). Thereafter, the total daily dose may be increased by 50 mg perday as tolerated every 3 days to reach 200 mg per day (50 mg four timesa day). After titration, 50 to 100 mg can be administered as needed forpain relief every 4 to 6 hours not to exceed 400 mg per day.

For patients for whom rapid onset of analgesic effect is required andfor whom the benefits outweigh the risk of discontinuation due toadverse events associated with higher initial doses, the analgesicsolution in a sufficient amount to provide 50 to 100 mg per day oftramadol or a pharmaceutically acceptable salt thereof (e.g., tramadolhydrochloride) can be administered as needed for pain relief every fourto six hours, not to exceed 400 mg per day.

Definitions/Abbreviations

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity. For example, an agent refers to one or more agents or atleast one agent. As such, the terms “a” (or “an”), “one or more”, and“at least one” can be used interchangeably herein. The use of thedefinite article (“the”) to refer to “an entity” refers to one or moreof that entity. For example, when the expression “the agent” refers tothe previously recitation of “an agent” it is understood that theexpression “the agent” refers to one or more agents.

The term “about” has its customary meaning, as defined in the USP,Section 8.20, which states that “about” indicates a quantity within 10%.

A stated amount for a compositional ingredient that is not preceded bythe term “about” does not mean that there is no variance for the statedterm, as one of ordinary skill would understand that there is alwayssome possibility of a degree of variability generally associated withexperimental error.

The concentration unit “% w/v” is a measure of the weight amount of aspecified ingredient based on the total volume of the composition.

As used herein, “substantially free” of a material may refer to an oralsolution where the material is present in an amount of less than 0.2%w/v, less than 0.1% w/v, less than 0.02% w/v, or less than 0.01% w/v inthe oral solution.

The terms “optional” or “optionally” as used herein means that asubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not.

The term “administration” or “administered” or “administering” as usedherein refers to administration of a unit dose of a compositiondescribed herein to a subject. The unit dose may be administered overrepeated time intervals, as needed.

q.d. (quaque die) means one a day.

b.i.d. (bis in die) means two times a day.

t.i.d. (ter in die) means three times a day.

q.i.d. (quater in die) means four times a day.

T_(max) refers to the observed time to reach a maximum plasmaconcentration.

C_(max) refers to the maximum plasma concentration.

AUC_(0-inf) refers to the area under the curve in a plot of analyteconcentration in blood plasma versus time from zero to infinity.

AUC_(0-t) refers to the area under the curve in a plot of analyteconcentration in blood plasma versus time from zero to a specified time.

t_(1/2) refers to the time required to eliminate one-half of the plasmaconcentration of an analyte.

Kel refers to the elimination rate constant.

ODMT means O-desmethyl-tramadol.

The expression “immediate release composition comprising tramadol” asused herein refers to ULTRAM® (tramadol hydrochloride) 50 mg tablet(U.S. New Drug Application No. 020281), for oral use, which isalternatively referred to herein as Reference Product or RLD. ULTRAM®tablets contain 50 mg of tramadol hydrochloride and are white in color.Inactive ingredients in the tablet are pregelatinized corn starch,modified starch (corn), hypromellose, lactose, magnesium stearate,microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodiumstarch glycolate, titanium dioxide and carnauba wax.

The terms “bioequivalence,” “bioequivalency,” or “bioequivalent,” asused herein is established by observing:

-   -   a) a 90% Confidence Interval between 80% and 125% for the ratio        (of Test Product vs. Reference Product) of the geometric mean of        AUC_(0-t) of tramadol and/or ODMT;    -   b) a 90% Confidence Interval between 80% and 125% for the ratio        (of Test Product vs. Reference Product) of the geometric mean        AUC_(0-inf) of tramadol and/or ODMT;    -   c) a 90% Confidence Interval between 80% and 125% for the ratio        (of Test Product vs Reference Product) of the geometric mean        C_(max) of tramadol and/or ODMT; or    -   d) a combination of any of a) to c).

The pharmaceutically acceptable salts of tramadol, as described herein,are acid addition salts wherein acid is selected from hydrochloric acid,hydrobromic acid, embonic acid, (2S,3S)-dibenzoyltartaric acid,dibenzoyltartaric acid, sebacic acid, 1-hydroxy-naphthoic acid,phosphoric acid, L-(+)-tartaric acid, lysinic acid, L-lysinic acid,D-(+)-malic acid, 4-methylbenzenesulfonic acid, ethanesulfonic acid,benzoic acid, cinnamic acid, L-(+)-lactic acid, S-(+)-mandelic acid,(+)-camphor-10-sulfonic acid, gluconic acid, L-(+)-ascorbic acid,ascorbic acid, palmitic acid, naphthalene-1,5-disulfonic acid, hexanoicacid, oleic acid, stearic acid, gentisic acid, octanoic acid, decanoicacid, nitric acid, orotic acid, mucic acid, alginic acid and acesulfamicacid, nicotinic acid, hydrogen bromide, sulfuric acid, acetic acid,propionic acid, oxalic acid, succinic acid, fumaric acid, maleic acid,hippuric acid, lactic acid, mandelic acid, malonic acid, malic acid,tartaric acid, methanesulfonic acid, citric acid, lactic acid.Preferably hydrochloric acid addition salt of tramadol is used for oralsolutions described herein.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 represents an 18 Day Titration Schedule for Tramadol OralSolution of 25 mg/5 mL or 50 mg/10 mL (viz., 5 mg/mL based on tramadolhydrochloride).

FIG. 2 represents an exemplary 18 Day Dosing Card for Tramadol OralSolution of 25 mg/5 mL or 50 mg/10 mL (viz., 5 mg/mL based on tramadolhydrochloride).

FIG. 3 represents an exemplary 18 Day Dosing Card for Tramadol OralSolution of 25 mg/5 mL or 50 mg/10 mL (viz., 5 mg/mL based on tramadolhydrochloride).

DETAILED DESCRIPTION

The information that follows details various embodiments of thedisclosure. For the avoidance of doubt, it is specifically intended thatany particular feature(s) described individually in any one of theseparagraphs (or part thereof) may be combined with one or more otherfeatures described in one or more of the remaining paragraphs (or partthereof). In other words, it is explicitly intended that the featuresdescribed below individually in each paragraph (or part thereof)represent aspects of the disclosure that may be taken in isolationand/or combined with other aspects of the disclosure. The skilled personwill appreciate that the claimed subject matter extends to suchcombinations of features and that these have not been recited in detailhere in the interests of brevity.

Oral Analgesic Solution

One embodiment is an oral analgesic solution for the treatment of paincomprising: (a) tramadol or a pharmaceutically acceptable salt thereofin an amount of from about 0.1% w/v to about 2.5% w/v; (b) a non-aqueoussolvent in an amount of from about 0 to about 30% w/v; (c) a tasteenhancer in an amount of from about 0% w/v to 30% w/v; (d) a sufficientamount of a buffer to maintain the pH of the oral solution from about 3to about 7; (e) a sweetener in an amount of from about 0.01% w/v toabout 1.0% w/v; (f) a flavoring agent in an amount of from about 0.1%w/v to about 5% w/v; (g) a preservative in an amount of from about 0%w/v to about 4% w/v; (h) optionally, a pH adjusting agent; and (i) asufficient amount of water.

In any one of the aspects disclosed herein, a sufficient amount of water(water refers to USP rated purified water that satisfies the USPrequirements for Purified Water, e.g., <643> for total organic carbonand <645> for water conductivity).

In any one of the aspects disclosed herein, the solution is free orsubstantially free of polyethylene glycol.

In any one of the aspects disclosed herein, the sole active ingredientin the solution is tramadol hydrochloride.

In one embodiment, the tramadol or a pharmaceutically acceptable saltthereof (a) comprises tramadol hydrochloride in an amount of from about0.45% w/v to about 0.55% w/v; the non-aqueous solvent (b) is present anamount of from about 0% w/v to about 10% w/v; the taste enhancer (c) ispresent in an amount of from about 0% w/v to 30% w/v; the buffer (d) ispresent in an amount of from about 0.20% w/v to about 0.40% w/v; thesweetener (e) is present in an amount of from about 0.01% w/v to about0.1%; the flavoring agent (f) is present in an amount of from about 0.2%w/v to about 0.4% w/v; and the preservative (g) is present in an amountof from about 0.2% w/v to about 0.4% w/v.

In another embodiment, the tramadol or a pharmaceutically acceptablesalt thereof (a) comprises tramadol hydrochloride in an amount of fromabout 0.45% w/v to about 0.55% w/v; the non-aqueous solvent (b) ispresent an amount from about 2% w/v to about 8% w/v; the taste enhancer(c) is present in an amount of from about 10% w/v to about 30% w/v; thebuffer (d) is present in an amount of from about 0.2% w/v to about 0.4%w/v; the sweetener (e) is present in an amount of about 0.01% w/v; theflavoring agent (f) is present in an amount of from about 0.2% w/v toabout 0.4% w/v; and the preservative (g) is present in an amount of fromabout 0.3% w/v to about 0.4% w/v.

One may appreciate that the buffer may be a pharmaceutically acceptablebuffer capable of obtaining a pH of the analgesic solution describedherein. Examples of buffers include, but are not limited to maleic acid,tartaric acid, lactic acid, citric acid, acetic acid, sodiumbicarbonate, sodium phosphate, or a combination thereof. In one aspect,the buffer may be a citrate buffer.

In another embodiment, the tramadol or a pharmaceutically acceptablesalt thereof (a) comprises tramadol hydrochloride in an amount of fromabout 0.45% w/v to about 0.55% w/v; the non-aqueous solvent (b)comprises propylene glycol in an amount of from about 2% w/v to about 8%w/v; the taste enhancer (c) comprises glycerin in an amount of fromabout 10% w/v to about 30% w/v; the buffer (d) comprises a citratebuffer present in an amount of from about 0.2% w/v to about 0.4% w/v;the sweetener (e) comprises sucralose present in an amount of about0.01% w/v; the flavoring agent (f) comprises a grape flavor present inan amount of from about 0.2% w/v to about 0.4% w/v; and the preservative(g) comprises sodium benzoate in an amount of from about 0.3% w/v toabout 0.4% w/v.

In yet another embodiment, the tramadol or a pharmaceutically acceptablesalt thereof (a) comprises tramadol hydrochloride in an amount of fromabout 0.45% w/v to about 0.55% w/v; the non-aqueous solvent (b)comprises propylene glycol in an amount of about 5% w/v; the tasteenhancer (c) comprises glycerin in an amount of about 20% w/v; thebuffer (d) comprises a citrate buffer present in an amount of about 0.3%w/v; the sweetener (e) comprises sucralose present in an amount of about0.01% w/v; the flavoring agent (f) comprises a grape flavor present inan amount of about 0.3% w/v; and the preservative (g) comprises sodiumbenzoate in an amount of about 0.375% w/v; and wherein the solution hasa pH of from about 4.5 to about 5.5.

In yet another embodiment, the tramadol or a pharmaceutically acceptablesalt thereof (a) comprises tramadol hydrochloride in an amount of fromabout 0.45% w/v to about 0.55% w/v; the non-aqueous solvent (b)comprises propylene glycol in an amount of about 5% w/v; the tasteenhancer (c) comprises glycerin in an amount of about 20% w/v; thebuffer (d) comprises a citrate buffer present in an amount of about 0.3%w/v; the sweetener (e) comprises sucralose present in an amount of about0.07% w/v; the flavoring agent (f) comprises a grape flavor present inan amount of about 0.3% w/v; and the preservative (g) comprises sodiumbenzoate in an amount of about 0.375% w/v; and wherein the solution hasa pH of from about 4.8 to about 5.4.

In a particular embodiment of any of the solutions described herein, theanalgesic solution has a pH of about 5, or about 5.1.

In one embodiment of any of the solutions described herein, the solutionexhibits an amount of tramadol hydrochloride of from about 0.45% w/v toabout 0.55% w/v after storage at 25±2° C. and 40±5% relative humidity(RH) in a container for 24 months.

In another embodiment of any of the solutions described herein, thesolution exhibits an amount of tramadol hydrochloride of from about0.48% w/v to about 0.53% w/v after storage at 25±2° C. and 40±5%relative humidity in a container for 24 months.

In yet another embodiment of any of the solutions described herein, thesolution exhibits an amount of tramadol hydrochloride of from about0.49% w/v to about 0.51% w/v after storage at 25±2° C. and 40±5%relative humidity in a container for 24 months.

In yet another embodiment of any of the solutions described herein, thesolution exhibits an amount of tramadol hydrochloride having a purity ofat least 99.4% by HPLC after storage at 25±2° C. and 40±5% relativehumidity in a container for 24 months.

In yet another aspect, a packaged oral solution as described hereinexhibits a tramadol hydrochloride assay amount of at least 99.4% after a24 month period while stored at 25±2° C. and 40±5% relative humidity.

A further aspect relates to a packaged oral solution as described hereinhaving an amount of either Compound A or Compound B of not more than0.20% by HPLC after a 24 month period while stored at 25±2° C. and 40±5%relative humidity.

A further aspect relates to a packaged analgesic solution of Aspect 5 orAspect 6 having an amount of total impurities (e.g., Compounds A, B, C,D, and/or E) of not more than 1.0% by HPLC after a 24 month period whilestored at 25±2° C. and 40±5% relative humidity.

In one embodiment of any of the oral solutions described herein, thesolution is bioequivalent to an immediate release tablet composition(such as 50 mg ULTRAM® tablets, NDA No. 020281) comprising tramadol whenadministered to an adult human under fasted conditions.

In one embodiment of any of the oral solutions described herein, thesolution is bioequivalent to an immediate release tablet compositioncomprising tramadol when administered to an adult human under fedconditions.

Based on bioequivalence testing conducted on human subjects, observedpharmacokinetic (“PK”) data (e.g., were measured for tramadol andO-desmethyl-tramadol (“ODMT”)) under fasted and fed conditions. Theobserved PK data from the bioequivalence testing were: (i) Cmax(tramadol, fasted): 170±50 ng/mL; AUC0-inf (tramadol, fasted): 1635±810ng/mL; (ii) Cmax (ODMT, fasted): 47±23 ng/mL; AUC0-inf (ODMT, fasted):644±275 hr*ng/mL; (iii) Cmax (tramadol, fed): 170±50 ng/mL; AUC0-inf(tramadol, fed): 1635±810 ng/mL; and (iv) Cmax (ODMT, fed): 47±23hr*ng/mL; AUC0-inf (ODMT, fed): 644±275 hr*ng/mL.

In one embodiment of any of the oral solutions described herein, thesolution exhibits a tramadol Cmax of from about 120 ng/mL to about 220ng/mL and an O-desmethyltramadol Cmax of from about 24 ng/mL to about 70ng/mL following administration of the solution to an adult human underfasted conditions. In one embodiment, the solution is bioequivalent toan immediate release tablet composition comprising tramadol whenadministered to an adult human under fasted conditions.

In one embodiment of any of the oral solutions described herein, thesolution exhibits a tramadol AUC0-inf of from about 825 hr*ng/mL toabout 2445 hr*ng/mL and an O-desmethyltramadol AUC0-inf of from about370 hr*ng/mL to about 920 hr*ng/mL following administration of thesolution to an adult human under fasted conditions. In one embodiment,the solution is bioequivalent to an immediate release tablet compositioncomprising tramadol when administered to an adult human under fastedconditions.

Yet another embodiment is a process for preparing the oral solution asdescribed herein by a process substantially as described herein. In oneembodiment, the process comprises adding ingredients (a) through (g),and a first suitable amount of water to a suitable vessel to obtain afirst solution, optionally adjusting the pH of the first solution to apH of about 3.1 with a suitable amount of aqueous hydrochloric acid, andadding a second suitable amount of water to the optionally pH-adjustedsolution.

One embodiment is an analgesic solution prepared by this process.

Yet another embodiment is a method of treating pain in a subject in needthereof, which comprises administering to the subject an effectiveamount of the analgesic solution of any one of an oral solutiondescribed herein.

Studies have shown that ULTRAM® is useful for the treatment of chronicpain in elderly human patients associated with, for example,osteoarthritis and chronic low-back syndrome. Thus, aspects contemplatedherein relate to a method for the treatment of one of osteoarthritis andchronic low-back syndrome.

Kit and Dosing Regimen

As stated elsewhere, the analgesic solution may be packaged in apharmaceutically acceptable container wherein the analgesic solution ispackaged with a volume that ranges from about 5 mL to about 100 mL,including all volume amounts in between, such as, for example, about 10mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL,about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about65 mL, about 70 mL, about 75 mL, about 80 mL, about 85 mL, about 90 mL,and about 90 mL.

In certain instances, it may be advantageous to package the analgesicsolution disclosed herein in a volume of about 5 mL or about 10 mL. Forexample, an analgesic solution comprising tramadol or a pharmaceuticallyacceptable salt thereof having an amount of tramadol (based on thehydrochloride salt) of about 5 mg/mL permits administration of a dosageamount of tramadol, e.g., 25 mg (for a volume of about 5 mL) or 50 mg(for a volume of about 10 mL). For instance, an analgesic solutioncomprising about 5 mg/mL tramadol hydrochloride permits administrationof a dosage amount of tramadol, e.g., 25 mg (for a volume of about 5 mL)or 50 mg (for a volume of about 10 mL).

The package may be in a suitable form acceptable to the end-user,including, for example, a cup, a vial, or a stick, each of which may besealed to prevent spillage of the analgesic solution and to minimizeintroduction of an external contaminant. The container and, ifapplicable, its components, may comprise a pharmaceutically acceptableplastic. Further aspects disclosed herein relate to a kit.

A cup having a volume of about 7 mL may be used for a dosage volume ofabout 5 mL, while a cup having a volume of about 15 mL may be used for adosage volume of about 10 mL.

The package, such as, a cup, may comprise a pharmaceutically acceptableplastic, including, for example, a high density polyethylene (“HDPE”), alow density polyethylene (“LDPE”), a linear low density polyethylene(“LLDPE”), a polypropylene (“PP”), a vulcanized thermoplastic (“TPV”)comprised of a PP and an ethylene propylene diene monomer rubber(“EDPM”), a polyethylene copolymer, or a combination thereof. In oneaspect, the package, such as a cup, comprises a HDPE.

The package, such as, a cup, may further comprise a colorant, forexample, an amber colorant such as that described in DMF No. 33315 heldby Polyone Corp, related to CC10292873XX (or Amber PE, CC10292873). Inanother aspect, the package, such as a cup, comprises a HDPE and anamber colorant having a light transmission of not more than 10% between290 and 450 nm, measured according to USP <671>.

In one aspect, the cup has a volume of about 15 mL capable of holding avolume (e.g., about 10 mL) of an analgesic solution described herein.The cup has an outer diameter (top) that ranges from about 1.99 to about2.02 inches (as measured by a micrometer).

In another aspect, the cup has a volume of about 7 mL capable of holdinga volume (e.g., about 5 mL) of an analgesic solution described herein.

Cups described containing an analgesic solution described hereincomprise a removable cup liner adhered thereto. For a cup having volumeof about 17 mL, the removable liner has a width of about 2.5 inches (asmeasured by a micrometer) and comprises a pharmaceutically acceptablepolymeric material, such as, for example a polyethylene terephthalate,which complies with USP <197> and USP <661>. One may appreciate that thecup liner adhesive comprises a pharmaceutically acceptable adhesive,including, for example, an adhesive comprising poly(ethylene-vinylacetate), which complies with USP <197> and USP <661>.

One embodiment is a kit comprising a container that comprises theanalgesic solution of any embodiment described herein and a writtenmaterial describing the use of the packaged analgesic solution for thetreatment of pain in a subject.

In one embodiment, the container comprises a volume of the analgesicsolution of about 5 mL or about 10 mL.

In another embodiment, the container is a cup having a volume of about 7mL or about 15 mL.

In yet another embodiment, the cup has a volume of about 7 mL and saidcup comprises a HDPE and an amber colorant, said cup having a lighttransmission of not more than 10% between 290 and 450 nm, measuredaccording to USP <671>.

In yet another embodiment, the cup has a volume of about 15 mL and saidcup comprises a HDPE and an amber colorant, said cup having a lighttransmission of not more than 10% between 290 and 450 nm, measuredaccording to USP <671>.

In another aspect related to the kit-container, the solution exhibits anamount of tramadol hydrochloride of from about 0.45% w/v to about 0.55%w/v after storage at 25±2° C. and 40±5% relative humidity after storagein a container for 24 months.

In yet another aspect related to the kit-container, the solutionexhibits an amount of tramadol hydrochloride of from about 0.48% w/v toabout 0.53% w/v after storage at 25±2° C. and 40±5% relative humidityafter storage in a container for 24 months.

In a further aspect, the kit-container comprises about 5 mL or about 10mL of the analgesic solution of any embodiment described herein and thesolution exhibits an amount of tramadol hydrochloride of from about0.49% w/v to about 0.51% w/v after storage at 25±2° C. and 40±5%relative humidity after storage in a container for 24 months.

In another aspect, the kit-container comprises about 5 mL or about 10 mLof the analgesic solution of any embodiment described herein and theamount of tramadol hydrochloride has a purity of at least 99.4% by HPLCafter storage at 25±2° C. and 40±5% relative humidity after storage inthe kit-container for 24 months.

In an additional aspect, the kit-container comprises about 5 mL or about10 mL of the analgesic solution of any embodiment described herein andthe tramadol hydrochloride assay amount of at least 99.4% after a 24month period while stored at 25±2° C. and 40±5% relative humidity.

In another aspect, the kit-container comprises about 5 mL or about 10 mLof the analgesic solution of any embodiment described herein having anamount of either Compound A or Compound B of not more than 0.20% by HPLCafter a 24 month period while stored at 25±2° C. and 40±5% relativehumidity. In yet a further aspect, the kit-container comprises about 5mL or about 10 mL of the analgesic solution of any embodiment describedherein having an amount of total impurities (e.g., Compounds A, B, C, D,and/or E) of not more than 1.0% by HPLC after a 24 month period whilestored at 25±2° C. and 40±5% relative humidity.

In one embodiment, the written material includes a dosing regimensubstantially as described in any one of FIGS. 1-3 . Although FIG. 3depicts what might be referred to as a “cup,” it is contemplated hereinthat the “cup” image may be a vial, a stick, or another pharmaceuticallyacceptable container.

Again, studies have shown that ULTRAM® is useful for the treatment ofchronic pain in elderly human patients associated with, for example,osteoarthritis and chronic low-back syndrome. Thus, the written materialmay further comprise instructions to treat at least one ofosteoarthritis and chronic low-back syndrome.

Yet another embodiment is a regimen for the treatment of pain, whichcomprises administering a subject in need thereof, about 25 mg oftramadol hydrochloride on days 1-3; about 50 mg of tramadolhydrochloride on days 4-6; about 75 mg of tramadol hydrochloride on days7-9; about 100 mg of tramadol hydrochloride on days 10-12; about 150 mgof tramadol on days 13-15; and about 200 mg of tramadol hydrochloride ondays 16-28 and thereafter, in the form of an analgesic solution of anyembodiment described herein, whereby discontinuations due to adverseside effects are reduced.

Yet another embodiment is a regimen for the treatment of pain, whichcomprises administering to subject in need thereof about 25 mg oftramadol hydrochloride on days 1-3; about 50 mg of tramadolhydrochloride on days 4-6; about 75 mg of tramadol hydrochloride on days7-9; about 100 mg of tramadol hydrochloride on days 10-12; about 150 mgof tramadol hydrochloride on days 13-15; and about 200 mg of tramadolhydrochloride on day 16 and thereafter, in the form of an analgesicsolution of any embodiment described herein, whereby discontinuationsdue to adverse side effects are reduced.

Yet another embodiment is a regimen for the treatment of pain accordingwhich comprises administering to subject in need thereof about 25 mg oftramadol hydrochloride q.d. on days 1-3, about 25 of mg of tramadolhydrochloride b.i.d. on days 4-6, about 25 mg of tramadol hydrochloridet.i.d. on days 7-9, about 25 mg of tramadol hydrochloride q.i.d. on days10-12, and about 50 mg of tramadol hydrochloride t.i.d. on days 13-28 inthe form of the analgesic solution of any embodiment described herein,whereby discontinuations due to adverse side effects are reduced.

Again, studies have shown that ULTRAM® is useful for the treatment ofchronic pain in elderly human patients associated with, for example,osteoarthritis and chronic low-back syndrome. Thus, aspects contemplatedherein relate to a method for the treatment of one of osteoarthritis andchronic low-back syndrome.

And in one aspect, the analgesic solution disclosed herein may beapplicable for the treatment of pain in a veterinary setting (e.g., usein dog and/or cats). Generally, a dose of tramadol (e.g., tramadolhydrochloride) in a veterinary setting ranges from about 1 to about 4mg/kg, administered b.i.d., t.i.d., or in certain instances q.i.d.

One will appreciate that, where applicable, the expression “comprising”may be replaced by expression “consisting of” or “consisting essentiallyof” without departing from the information disclosed herein.

Examples

The analgesic solutions described herein was characterized by numeroustests, including: appearance; pH, USP <791>; Weight Loss (“Wt. Loss”),USP <671>; anti-microbial effectiveness testing, USP <51>;microbiological examination, USP <61>; and USP <62>, and specificgravity/density, USP <841>, Method I. Additionally, high performanceliquid chromatography analysis, see generally, USP <621>, was performedon the analgesic solutions described herein for the followingobservables: Tramadol Hydrochloride Assay, Sodium Benzoate (“SB”) Assay,Unspecified and Unidentified Impurities (“UU Imps.”), and TotalImpurities (“Total Imps.”). Suitable HPLC methods include thosedescribed in Kartinasari et al., HPLC Determination and Validation ofTramadol Hydrochloride in Capsules, J. Liq. Chromat Related Tech. (2004)27(4):737-744 (“Kartinasari”) or Tramadol Hydrochloride, USP-NF, 2013(“Tramadol HCl USP”). Assay and impurities may be identified and/orcalculated from the HPLC results, as described in, for example,Bleisner, D. M., “Appendix V: Template for An Example Standard TestMethod,” in Validating Chromatographic Methods—A Practical Guide,Wiley-Interscience, 2006, pp. 159-168 (doi:10.1002/0470042206.app5)(“Bleisner”) and Venkanna et al., Synthesis of related substances ofTramadol hydrochloride, analgesic drug, J. Chem. Pharm. Res. (2014)4(10): 4506-4513 (“Venkanna”).

A substantial amount of development work was undertaken to achieve thesolutions disclosed and claimed herein. Table 1 represents a summary ofseven exemplary solutions.

TABLE 1 Summary of tramadol hydrochloride oral solutions Example 1 2 3 45 6 7 Ingredient Ingredient Amounts, % w/v Tramadol HCl USP 0.50 0.500.50 0.50 0.50 0.50 0.50 Citric Acid, anhydrous USP 0.20 0.20 — 0.100.10 0.10 0.10 Trisodium Citrate, 0.05 0.05 — 0.25 0.20 0.20 0.20dihydrate USP Sodium Phosphate, — 0.20 — — — — Monobasic, MonohydrateSodium Phosphate, — 0.15 — — — — Dibasic Grape Flavor 0.30 0.30 0.300.30 0.30 0.30 0.30 Propylene Glycol USP 5.00 5.00 10.00 5.00 5.00 5.005.00 Glycerin USP — — — — 20.0 20.0 20.0 Sucralose MP NF 0.01 0.01 0.010.01 0.07 0.07 0.07 Sodium Benzoate NF 0.30 0.30 — 0.30 0.375 0.3750.375 Methylparaben NF — 0.15 — — — — Propylparaben NF — 0.05 — — — — pH(initial) 4.0 4.4 6.5 5.0 — — — 5 N HCl q.s. — — — — — — 2.5 N NaOH q.s.q.s. — — — — pH (final) 3.1 5.1 7.1 5.1 5.1 5.0 5.1 Purified Water USPq.s. q.s. q.s. q.s. q.s. q.s. q.s. Batch Volume (L) 0.5 0.5 0.5 1.0 250250 2000 Density (g/mL) ND ND ND 1.006 1.05 1.05 1.05

The Example 1 solution was prepared by adding Propylene Glycol USP,Purified Water USP, Citric Acid, anhydrous USP, Trisodium Citrate,dihydrate USP, Sucralose micronized powder (“MP”) NF (which has a d9θ<12microns), Sodium Benzoate NF, Tramadol HCl USP, and Grape Flavor to asuitably sized container. The initial pH of 4.0 was adjusted to a pH of3.05 with about 5 mL of 5 N HCl. A sufficient amount (q.s.) of PurifiedWater USP to about 500 mL (0.5 L) was then added. All materials readilydissolved in under 1 minute. The Example 1 solution was packaged in10×50 mL 2 oz. white PET bottles. A taste test of the Example 1 solutionshowed that there was an initial bitterness with some stinging.

Tramadol HCl and sodium benzoate assays performed by HPLC analysisshowed that the Example 1 solution exhibited labeled contents of 98.9%for tramadol and 98.4% for sodium benzoate. The viscosity of the Example1 solution was determined to be 1.14 to 1.40 cP (Brookfield ViscometerDV-II Pro (LV Spindle 00/25° C./60-100 rpm). A freeze-thaw test showedno signs of precipitation.

The Example 2 solution was prepared by adding Propylene Glycol USP,Purified Water USP, Citric Acid, anhydrous USP, Trisodium Citrate,dihydrate USP, Sucralose MP NF, Sodium Benzoate NF, Tramadol HCl USP,and Grape Flavor to a suitably sized container. The initial pH of 4.4was adjusted to 5.02 using about 1.5 mL of 2.5 N NaOH. A sufficientamount (q.s.) of Purified Water USP to about 500 mL (0.5 L) was thenadded. The Example 2 solution was packaged in 10×50 mL 2 oz. white PETbottles. A taste test of the Example 2 solution showed improvedqualities compared to the Example 1 solution (that is, there was noinitial bitterness with stinging). The taste may be improved, however.

The Example 3 solution was prepared by adding Propylene Glycol USP,Methylparaben NF, Propylparaben NF, Purified Water USP, SodiumPhosphate, Monobasic, Monohydrate, Sodium Phosphate, Dibasic, SucraloseMP NF, Tramadol HCl USP, and Grape Flavor to a suitably sized container.Parabens required 5 minutes stirring to dissolve. All other materialsreadily dissolved (<1 minute). A small amount of precipitate wasobserved after addition of Grape Flavor—an additional amount ofPropylene Glycol USP (25 g) was added and the composition was heated toabout 50° C. with stirring until a clear solution had formed. Theinitial pH of 6.5 was adjusted to 7.1 using about 1.5 mL of 2.5 N NaOH.A sufficient amount (q.s.) of Purified Water USP to about 500 mL (0.5 L)was then added. The Example 3 solution was packaged in 10×50 mL 2 oz.white PET bottles. A taste test of the Example 3 solution showed amostly bland taste with some aftertaste.

The solutions of Examples 1-3 were evaluated for pH stability andtramadol labeled content. Specifically, samples were evaluated for thepH and tramadol labeled content at four temperatures (viz., 25° C., 40°C., 55° C., and 70° C.) over four weeks. Table 2 summarizes the resultsof these stability tests.

TABLE 2 Test results of tramadol hydrochloride solutions at differentpH-values Parameter Conditions pH % L.C. Temp. Time, w Ex. 1 Ex. 2 Ex. 3Ex. 1 Ex. 2 Ex. 3 — 0 3.130 5.085 7.106 101.0  99.8  99.9 25° C. 2 3.0605.098 7.107  99.5  99.9  99.8 25° C. 4 3.158 5.096 7.030 100.2 100.7 99.3 40° C. 2 3.177 5.096 7.100 101.5 101.1 101.5 40° C. 4 3.143 5.0487.013 101.0 100.5  99.3 55° C. 2 3.142 5.103 7.038 100.8 100.6  96.6 55°C. 4 3.161 5.076 6.963 101.8 101.7  99.6 70° C. 2 3.138 5.095 6.817102.0 101.9  93.8 70° C. 4 3.175 5.066 6.639 103.9 103.8  95.9 % RSD1.1  0.4  2.2   1.2  1.2  2.5

The results of the stability tests show that the pH values of thesolutions of Exs. 1 and 2 remained relatively constant over the entiretesting period (cf. % relative standard deviation (RSD) of 1.1 (Ex. 1)and 0.4 (Ex. 2). However, the pH values of the solutions of Ex. 3 showedsome drift (cf. % RSD of 2.5). The percent of tramadol labeled content(% L.C.) remained relatively constant for Exs. 1 and 2, but the Ex. 3solution showed a tendency to reduce with time—especially at 70° C. Thisdata suggests that the Ex. 3 solution might have a limited roomtemperature shelf-life stability, e.g., less than 2 years. The datashowed that: (i) sodium benzoate is more efficacious in an acidicenvironment, (ii) tramadol HCl is freely soluble at a pH of about 4.5;and (iii) tramadol hydrochloride (with a pKa of 9.8) has a pH of about5.3. Therefore, the Ex. 2 solution was evaluated for further studies.

The Example 4 solution was prepared by adding Propylene Glycol USP andPurified Water USP (about 83% of the total solution requirement) to asuitably sized container and mixing for about 5 minutes at about 350rpm. Next, Citric Acid, anhydrous USP, Sodium Citrate dihydrate USP,Sucralose MP NF, and Sodium Benzoate NF were added in the specifiedamounts and mixed for about 10 minutes at about 350 rpm. The pH wasmeasured at this stage and then Tramadol HCl USP was added and thecomposition was mixed for about 10 minutes at about 350 rpm. The pH wasmeasured and the Grape Flavor was added followed by mixing for about 5minutes at about 350 rpm. A sufficient amount (q.s.) of Purified WaterUSP to about 1000 mL (1.0 L) was then added, and the pH of the solutionwas measured. The final pH-value was 5.14 and the density was 1.006g/mL.

The results of a preservative challenge study suggested increasing theamount of preservative (e.g., sodium benzoate). Thus, the Example 4solution was modified to increase the amount of preservative from 0.30%w/v to 0.375% w/v in Example 5. Additionally, the results of a tastetest prompted an added amount of a taste enhancer (e.g., glycerin).Thus, the Example 4 solution was modified by introducing a sufficientamount of taste enhancer (e.g., glycerin) for better taste and mouthfeel. The compositional makeup of the Examples 5, 6, and 7 solutionsrepresent the changes made to the Example 4 solution.

The solutions of Exs. 5 and 6 were manufactured with a Batch Volume of250 L, which required a 300 L working capacity stainless steel tank anda portable mixer equipped with a ¾″×603/4″ dimensional length shaft witha 6″ propeller.

The solution of Ex. 7 was manufactured with a Batch Volume of 2000 L,which requires a 2000 L working capacity stainless steel tank equippedwith a mixer rated at ¾ HP, 230V capable of 350 rpm, equipped with a¾″×71″ dimensional shaft and two 133/4″ propellers.

One or two 10″-1 micron filters were utilized depending on batch size.

The solutions of Exs. 5, 6, and 7 were manufactured as follows: (i) adda suitable amount of Purified Water USP (e.g., about 75% to 85% of thetotal amount) to the main mixing tank; (ii) turn on the mixer and addPropylene Glycol USP and Glycerin USP to the main mixing tank and mixfor a minimum of 5 minutes at a minimum of 350 rpm; (iii) add SodiumBenzoate NF, Citric Acid, anhydrous USP, Sodium Citrate dihydrate USP,and Sucralose MP NF to the main mixing tank and mix for a minimum of 10minutes at a minimum of 350 rpm; (iv) add Tramadol HCl USP to the mainmixing tank and mix for a minimum of 10 minutes at a minimum of 350 rpm;(v) add Grape Flavor to the main mixing tank and mix for a minimum of 5minutes at a minimum of 350 rpm; (vi) add a sufficient amount ofPurified Water USP to the main mixing tank to achieve the desired batchsize and mix for a minimum of 30 minutes at a minimum of 350 rpm; (vii)install 1 micron filter(s) and recirculate the product through thefilter and back into the processing tank for 5 minutes; (viii) performin-process testing: describe color and clarity, measure density and pH(remove samples as required for in-process release testing); and (ix)transfer the solution to a tote until packaged.

The solutions were packaged in a 16 oz. (480 mL fill) white high densitypolyethylene bottle with child-resistant closures.

Several parameters of the packaged solutions (Ex. 6) were evaluatedwhile storing the packaged solution at 25±2° C. and 40±5% relativehumidity (RH). The packages were maintained in two orientations (eitheron side or upright) for the entirety of the study period, which hasspanned for 24 months.

The evaluated parameters include: (i) appearance; (ii) TramadolHydrochloride (“THCl”) Assay; (iii) Sodium Benzoate (“SB”) Assay; (iv)Unspecified and Unidentified Degradants (“UU Imps.”); (v) TotalDegradants (“Total Imps.”); (vi) pH; and (vii) Weight Loss (“Wt. Loss”).

Tables 3 and 4 summarize the results of the evaluated parameters overthe 24-month period, where the reporting threshold (RT) is 0.1%.

TABLE 3  Evaluation of Packaged Solutions Storage Condition: 25 ± 2° C.;40 ± 5% RH, on side  Sample Age (mos.) Test Acceptance Criteria 0 3 6 912 18 24 Appearance Clear liquid CON CON CON CON CON CON CON THCl Assay90.0-110.0% L.C. 100.4 99.9 99.4 99.1 98.6 99.3 99.4 SB Assay80.0%-110.0%  99.6 99.3 99.0 98.7 98.5 99.2 99.2 UU Imps. ≤0.2% w/w <RT<RT <RT <RT <RT <RT <RT Total Imps. <1.0% <RT <RT <RT <RT <RT <RT <RT pH4.5-5.5  5.1  5.1  5.1  5.1  5.1  5.2  5.1 Wt. Loss NMT 5% N/A 0  0  0 0  0  0 Total impurities may include Compound A (viz.,RS,SR-1-(3-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexanolhydrochloride (i.e., the (±) trans-isomers)), Compound B (viz.,2-[(dimethylamino)methyl]cyclohexanone hydrochloride),[2-(3-methoxyphenyl)cyclohex-1-enyl]-N,N-dimethyl methanamine (CompoundC), (1RS)-[2-(3-methoxyphenyl)cyclohex-2-enyl]-N,N-dimethyl methanamine(Compound D), and/or(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-hydroxyphenyl)cyclohexanol(Compound E). Related Compound A is controlled with a specificationlimit of NMT 0.20%, while Related Compound B is controlled with aspecification limit of NMT 0.20%. Each of the individual unidentifiedimpurities is controlled with a specification limit of NMT 0.1%. Totalimpurities are controlled with a specification limit of NMT 1.0%.

TABLE 4  Evaluation of Packaged Solutions Storage Condition: 25 ± 2° C.;40 ± 5% RH, on side  Sample Age (mos.) Test Acceptance Criteria 0 3 6 912 18 24 Appearance Clear liquid CON CON CON CON CON CON CON THCl Assay90.0-110.0% L.C. 100.4 99.9 99.7 99.5 98.9 99.4 99.4 SB Assay80.0%-110.0%  99.6 99.4 99.5 99.1 98.9 99.0 99.2 UU Imps. ≤0.2% w/w <RT<RT <RT <RT <RT <RT <RT Total Imps. <1.0% <RT <RT <RT <RT <RT <RT <RT pH4.5-5.5  5.1  5.1  5.1  5.1  5.1  5.2  5.1 Wt. Loss NMT 5% N/A 0  0  0 0  0  0 

The results of Tables 3-4 shows that the packaged solution exhibits atramadol hydrochloride assay amount of at least 99.4% after a 24 monthperiod while stored at 25±2° C. and 40±5% relative humidity. Thus, apackaged solution disclosed and claimed herein is stable for at least a24 month period when stored at 25±2° C. and 40±5% relative humidity.

Additional parameters evaluated (associated tests and acceptancecriteria) include: (i) total aerobic microbial count (USP<61>, <200cfu/mL); (ii) total yeast and mold count (USP<61>, <20 cfu/mL); (iii)specified organism (E. coli) (USP<62>, Absent); (iv) specified organismB. cepacia (USP<62>, Absent); (v) Antimicrobial Effectiveness Testing(USP<51>, Conforms to USP for Category III Products); and (vi) PackageAssessment, Label adhering; no label cracks or fading; closure tight &seal intact). The packaged solutions conform to each of the additionalparameters over the entire study period.

BE Fasting Study

A bioequivalence (BE) study was designed to evaluate oral relativebioavailability study of tramadol HCl oral solution (50 mg/10 mL, Ex. 6,“Test Product” or “TP”) and ULTRAM® (tramadol HCl) 50 mg tablets(“Reference Product” or “RLD”), in healthy adult human subjects underfasting condition.

The primary objective of the study was to compare the rate and extent ofabsorption of tramadol in the Test Product and the Reference Product inhealthy adult human subjects under fasting condition. A secondaryobjective was to assess the safety and tolerability following oraladministration of tramadol oral solution.

The study was an open label, balanced, randomized, single dose, twotreatment, two period, two sequence, crossover oral relativebioavailability study of Test Product and Reference Product in healthyadult human subjects under fasting condition.

Healthy, male, adult human volunteers who were willing to participate inthe study and fulfill the inclusion and exclusion criteria were selectedfor the study. Volunteers aged from 19-42 years with a body mass index(BMI) in the range of 19.17 and 24.79 (both inclusive, calculated asweight in kg/height in m) were selected for the study. Subjects wereconfined within the testing facility from at least 11 hours before drugadministration to 48 hours after drug administration. Subjects wererandomized to either 10 mL of Test Product (viz., 50 mg dose) or onetablet of Reference Product (viz., 50 mg dose). The subjects consumeddinner at least 10 hours prior to dosing. Table 5 summarizes the mealschedule for the subjects.

TABLE 5 Meal schedule for Fasting Study Breakfast Lunch Snacks DinnerDay Time post dose (hr) Check-in day NA NA NA At least 10 hrs prior todosing Dosing day (D) NA 4 8 12 D + 1 day 24 28  32  36

As per the randomization schedule, in period-I, 18 subjects received theTest Product and 18 subjects received the Reference Product and inperiod-II, 17 subjects received the Test Product and 16 subjectsreceived Reference Product.

After overnight fasting of at least 10 hrs, subjects were administered asingle oral dose of the Test Product (T). After subjects swallowed theTest Product, the drug-dispensing syringe was rinsed with an adequateamount of water (from the given 240 mL of water used for drugadministration) for 2 to 3 times and swallowed the rinse. The remainingamount of drinking water from 240 mL was administered at roomtemperature in sitting position, under fasting condition.

After overnight fasting of at least 10 hours, one tablet of ReferenceProduct along with 240 mL of drinking water was administered orally tothe subjects in sitting position, at room temperature.

Drug administration was done as per the randomization schedule. Dosingfor the subjects started at 08:00 hours and completed at 08:22 hours inboth the periods in sitting position.

In each period, a total of 24 blood samples (1×5 mL each) in each periodat each time point) and in study total 48 blood samples were collectedas per the following schedule: Pre-dose (0 hour) sample within 1 hourprior to drug administration and the others at 0.25, 0.50, 0.75, 1.00,1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 5.00, 6.00,8.00, 10.00, 12.00, 16.00, 24.00, 36.00 and 48.00 hrs post dose into 5mL K₂EDTA vacutainers over ice. Once blood samples from each time pointwere collected, they were transferred for centrifugation at 3800 rpm for10 minutes at 4° C.±2° C. The plasma was then be separated, transferredinto two aliquots of properly labeled polypropylene tubes. The timeinterval between sample collection and the start of centrifugation didnot exceed 30 minutes. Freeze plasma samples immediately (within 60minutes) from the sample collection time. Plasma Samples were stored at−70° C.±15° C. until drawn for analysis. Analysis of Tramadol andO-desmethyltramadol in plasma concentration was performed by a validatedLC-MS/MS analytical method.

A wash out period of at least 7 days was maintained between eachconsecutive drug administration to minimize the carry over effects andto eliminate the drug from the body. Pharmacokinetic parameters of theTest Product and Reference Product were assessed.

Pharmacokinetic measurements are the concentrations of the drug in theplasma over a period when the samples taken. From the time/concentrationvalues, various Pharmacokinetic parameters Cmax, AUC0-t, AUC0-inf, Tmax,t½ and Kel for tramadol and O-desmethyltramadol were calculated andthese were used in the statistical analysis to compare the relativebioavailability of the two products.

Cmax, AUC0-t and AUC0-inf for tramadol were considered as primarypharmacokinetic variables. The acceptance range for bioequivalence is80-125% for 90% confidence intervals for the ratio of least square meansof the ln-transformed primary pharmacokinetic variables.

Pharmacokinetic parameters were calculated using Phoenix® WinNonlin®Version 6.3. The Mean, Standard Deviation, Minimum, Median, Maximum andCoefficient of Variation were calculated for plasma concentrations ofTramadol and O-desmethyltramadol for each sampling time, treatment andfor Cmax, AUC0-t, AUC0-inf, Tmax, t½ and Kel for tramadol andO-desmethyltramadol. The calculation of these pharmacokinetic parameterswas explained below.

Cmax, the maximum observed concentration and Tmax, the time to reachthat peak concentration, were determined for each subject and for eachtreatment.

To calculate the elimination rate constant (Kel), regression analysiswas performed on the natural log (Ln) of plasma concentration values(Y-axis) versus time (X-axis). Calculations were made between a timepoint where log-linear elimination phase begins (TLIN) and the time atwhich the last concentration above the limit of quantitation (LQCT)occurred. The Kel was taken as the slope multiplied by (−1) and theapparent half-life (t_(1/2)) as (ln 2)/Kel.

AUC0-t was calculated using the linear trapezoidal rule.

The AUC_(0-inf) was calculated as: AUC0-t+Ct/Kel, where Ct is the lastobserved non-zero concentration for that treatment, AUC0-t is the AUCfrom time zero to the time of the last non-zero concentration for thattreatment, and Kel is the elimination rate constant.

The analysis of variance (“ANOVA”) was performed on the ln-transformeddata Cmax, AUC0-t, AUC0-inf for tramadol and O-desmethyltramadol. Allstatistical analyses were performed using SAS® software (version 9.4 forwindows).

For all analyses, Period and Treatment effects were consideredstatistically significant if the probability associated with ‘F’ lessthan 0.05 and for sequence effect less than 0.10.

The 90% geometric confidence intervals for ln-transformed C_(max),AUC0-t and AUC0-inf for tramadol and O-desmethyltramadol weredetermined.

ANOVA was estimated at alpha 0.05 on the ln-transformed PK ParametersCmax, AUC0-t and AUC0-inf for tramadol and O-desmethyltramadol. Theanalysis of variance model include sequence, subject nested withinsequence, period and treatment as factors. The significance of thesequence effect at alpha (α) 0.10 was tested using the subject nestedwithin the sequence as the error term.

A total of 33 subject samples were utilized for pharmacokinetic andstatistical analysis. There was no significant effect found in the studyfor ln-transformed pharmacokinetic parameters Cmax, AUC0-t, AUC0-inf forTramadol.

Table 6 summarizes the pharmacokinetic (“PK”) results for tramadol andO-desmethyltramadol (ODMT) observed for bioequivalence study for TestProduct (TP) and Reference Product (RLD). With the exception of Tmax(reported as a median value and minimum and maximum ranges), theremaining PK values are reported as arithmetic means with correspondingstandard deviations.

TABLE 6 Summary of PK Results for Tramadol and ODMT BE Fasting studyTramadol ODMT TP RLD TP RLD Parameters Mean ± SD Mean ± SD Mean ± SDMean ± SD Tmax (hr) # 1.5 (0.5-2.5) 1.5 (0.75-3.00) 2.0 (0.5-5.0) 2.25(1.25-10.00) Cmax (ng/mL) 180.20 ± 33.81 173.51 ± 29.59 47.77 ± 19.0646.14 ± 18.28 AUC0-t (hr * ng/mL) 1623.92 ± 502.43 1681.64 ± 578.06624.12 ± 205.58 624.10 ± 199.82 AUC0-inf 1658.31 ± 525.97 1721.47 ±624.72 638.95 ± 207.18 639.26 ± 198.04 (hr * ng/mL) t½ (hr)  7.65 ± 1.63 7.61 ± 1.82 7.9 ± 1.6 8.1 ± 2.1 Kel (hr-1)  0.095 ± 0.023  0.096 ±0.022 0.091 ± 0.019 0.090 ± 0.019 # Median value for Tmax median with anassociated minimum and maximum range.

One may determine the coefficient of variation (or relative standarddeviation), defined as the ratio of the standard deviation (SD) to thearithmetic mean (mean), to determine the extent of variability inrelation to the mean of the sample population.

Least squares geometric means, ratio of means, and 90% geometricconfidence intervals were also determined for the Test Product (TP) andReference Product (RLD), the results of which are presented in Table 7.

TABLE 7 Least squares geometric means, ratio of means, and 90% geometricconfidence intervals of tramadol and ODMT for TP and RLD PK-value TP RLDRatio, % 90% C.I. Tramadol AUC0-t 1553.79 1609.16  96.56 93.62-99.59(hr * ng/mL) AUC0-inf 1584.24 1641.66  96.50 93.51-99.59 (hr * ng/mL)Cmax (ng/mL)  177.46  171.35 103.56  98.68-108.70 ODMT AUC0-t  578.40 580.08  99.71  96.84-102.66 (hr * ng/mL) AUC0-inf  594.09  597.87 99.37  96.41-102.42 (hr * ng/mL) Cmax (ng/mL)  42.75  40.99 104.29 99.70-109.08

As related to Cmax for tramadol, the Test/Reference ratio of geometricmeans was 103.56% and the 90% confidence interval for the ratios of theln-transformed means was found to be 98.68-108.70%. The confidenceinterval was within the acceptance limits of 80-125% required for theconclusion of bioequivalence.

As related to Cmax for ODMT, the Test/Reference ratio of geometric meanswas 104.29% and the 90% confidence interval for the ratios of theln-transformed means was found to be 99.70-109.08. The confidenceinterval was within the acceptance limits of 80-125%.

As related to AUC0-t for tramadol, the Test/Reference ratio of geometricmeans was 96.56% and the 90% confidence interval for the ratios of theln-transformed means was found to be 93.62-99.59%. The confidenceinterval was within the acceptance limits of 80-125% required for theconclusion of bioequivalence.

As related to AUC0-t for ODMT, the Test/Reference ratio of geometricmeans was 99.71% and the 90% confidence interval for the ratios of theln-transformed means was found to be 96.84-102.66%. The confidenceinterval was within the acceptance limits of 80-125%.

As related to AUC0-inf for tramadol, the Test/Reference ratio ofgeometric means was 96.50% and the 90% confidence interval for theratios of the ln-transformed means was found to be 93.51-99.59%. Theconfidence interval was within the acceptance limits of 80-125% requiredfor the conclusion of bioequivalence.

As related to AUC0-inf for ODMT, the Test/Reference ratio of geometricmeans was 99.37% and the 90% confidence interval for the ratios of theln-transformed means was found to be 96.41-102.42. The confidenceinterval was within the acceptance limits of 80-125%.

Food Effect and Fed Bioequivalence Study

An open label, balanced, randomized, single dose, three treatment, threeperiod, three sequence, crossover, oral food effect and fedBioequivalence study of Tramadol HCl oral solution (50 mg/10 mL, Ex. 7)and ULTRAM® (tramadol HCl) 50 mg tablets in healthy adult humansubjects.

Volunteers aged from 24-42 years with a body mass index (BMI) in therange of 20.68 and 24.66 (both inclusive, calculated as weight inkg/height in m) were selected for the study.

The study included two primary objectives: (1) to evaluate the effect offood on the rate and extent of absorption of Tramadol HCl oral solution(50 mg/10 mL) in healthy adult human subjects and (2) to compare therate and extent of absorption of Tramadol HCl oral solution (50 mg/10mL) and ULTRAM® (tramadol HCl) 50 mg tablets in healthy adult humansubjects under fed condition. A secondary objective was to assess thesafety and tolerability following oral administration of Tramadol HCloral solution.

No adverse effects were reported during the study period.

An open label, balanced, randomized, single dose, three treatment, threeperiod, three sequence, crossover, oral food effect and fedBioequivalence study in healthy adult human subjects. Subjects underwentscreening evaluation to determine eligibility within 28 days prior tothe check in of 1st period. Subjects were confined within the facilityfrom at least 11 hours before drug administration to 48 hours after drugadministration. Subjects were randomized to either ‘ABC’ or ‘BCA or CAB’(where A=Test Product under fed condition, B=Test Product under fastingcondition and C=Reference Product under fed condition) and were dosedwith 240 mL of water at room temperature in sitting position.

As per the randomization schedule, in Period-I, Period-II, andPeriod-III, six subjects received the Test Product (A), six subjectsreceived Test product (B), and six subjects received Reference product(C).

Treatment A administration: After overnight fasting of at least 10hours, a high-fat high-calorie non vegetarian breakfast was served about30 minutes prior to administration of Tramadol HCl oral solution (50mg/10 mL). The Test Product was administered 30 minutes after start ofthe high-fat high-calorie non vegetarian breakfast. 10 mL of TestProduct was administered orally to the subjects in a sitting positionwith 240 mL of water, at ambient temperature in each period as per therandomization schedule.

Treatment B administration: After overnight fasting of at least 10.00hours, 10 mL of Test Product was administered orally to the subjects insitting position with 240 mL of water, at ambient temperature in eachperiod as per the randomization schedule.

After subjects swallowed the Test Product, the drug-dispensing container(syringe) was rinsed with an adequate amount of water (from the given240 mL of water used for drug administration) for 2 to 3 times andswallow the rinse. The remaining amount of drinking water from 240 mLwas administered at room temperature in a sitting position.

Treatment C administration: After overnight fasting of at least 10hours, a high-fat high-calorie non vegetarian breakfast was served about30 minutes prior to administration of one tablet of Reference Product,which was administered orally to the subjects in a sitting position with240 mL of water, at ambient temperature in each period as per therandomization schedule. Subjects were instructed not to chew or crushthe tablet (Reference Product) and swallow as a whole. Compliance fordosing were assessed by a thorough check of the oral cavity immediatelyafter dosing.

Table 8 summarizes the meal schedule for the subjects of the fed/fastingstudy.

TABLE 8 Meal schedule for Fed/Fasting Study Breakfast Lunch SnacksDinner Day Time post dose (hr) Check-in day NA NA NA At least 10 hrsprior to dosing Dosing day (D) A (Yes)/B (No)/ 4 8 12 C (Yes) D + 1 day24 28  32  36

Blood samples were taken as described above. Pharmacokineticmeasurements are the concentrations of the drug in the plasma over aperiod when the samples taken. From the time/concentration values,various PK parameters Cmax, AUC0-t, AUC0-inf, Tmax, t½ and Kel. Tramadoland O-desmethyltramadol were calculated and these were used in thestatistical analysis to compare the relative bioavailability and foodeffect of the two products, as explained above.

Table 9 summarizes the PK results for tramadol and O-desmethyltramadolobserved for Treatment A (viz., tramadol hydrochloride oral solution (50mg/10 mL) administered under fed conditions) and Treatment C (viz.,ULTRAM® (tramadol HCl, tablets, 50 mg) administered under fedconditions). With the exception of Tmax (reported as a median value andminimum and maximum ranges), the remaining PK values are reported asarithmetic means with corresponding standard deviations.

TABLE 9 Summary of PK Results for Treatment A and Treatment C under FedConditions Tramadol ODMT A C A C Parameters Mean ± SD Mean ± SD Mean ±SD Mean ± SD Tmax (hr) # 2.0 (0.5-3.5) 1.9 (0.75-4.00) 3.50 (1.75-5.00)2.13 (1.00-5.00) Cmax (ng/mL) 146.22 ± 28.50 186.63 ± 32.87 41.35 ±11.53 44.79 ± 14.05 AUC0-t (hr * ng/mL) 1606.04 ± 574.38 1650.63 ±514.55 623.14 ± 167.54 626.76 ± 143.85 AUC0-inf (hr * ng/mL) 1635.90 ±594.44 1681.64 ± 536.06 635.05 ± 169.97 639.90 ± 145.57 t½ (hr)  7.33 ±1.19  7.42 ± 1.42 7.6 ± 1.1 7.7 ± 1.2 Kel (hr-1)  0.097 ± 0.015  0.097 ±0.020 0.094 ± 0.014 0.092 ± 0.014 # Median value for Tmax median with anassociated minimum and maximum range.

Least squares geometric means, ratio of means, and 90% geometricconfidence intervals were also determined for the Test Product (T) andReference Product (R), N=18, the results of which are presented in Table10.

TABLE 10 Least squares geometric means, ratio of means, and 90%geometric confidence intervals based on tramadol and ODMT for TreatmentA and Treatment C PK-value A C Ratio, % 90% C.I. Tramadol AUC0-t 1515.801580.46 95.91 92.49-99.45 (hr * ng/mL) AUC0-inf 1541.65 1607.66 95.8992.41-99.51 (hr * ng/mL) Cmax (ng/mL) 143.62 183.86 78.12 73.25-83.31ODMT AUC0-t 601.08 609.96 98.54  94.43-102.84 (hr * ng/mL) AUC0-inf612.89 623.17 98.35  94.34-102.53 (hr * ng/mL) Cmax (ng/mL) 39.54 42.7792.47 87.22-98.03

As related to AUC0-t for tramadol, the Test (A)/Reference (C) ratio ofgeometric means was 95.91% and the 90% confidence interval for theratios of the ln-transformed means was found to be 92.49-99.45%. And forODMT, the Test (A)/Reference (C) ratio of geometric means was 98.54% andthe 90% confidence interval for the ratios of the ln-transformed meanswas found to be 94.43-102.84%.

As related to AUC0-inf for tramadol, the Test (A)/Reference (C) ratio ofgeometric means was 95.89% and the 90% confidence interval for theratios of the ln-transformed means was found to be 92.41-99.51%. And forODMT, the Test (A)/Reference (C) ratio of geometric means was 98.35% andthe 90% confidence interval for the ratios of the ln-transformed meanswas found to be 94.34-102.53%.

As related to Cmax, the Test (A)/Reference (C) ratio of geometric meanswas 78.12% and the 90% confidence interval for the ratios of theln-transformed means was found to be 73.25-83.31% of Tramadol. The Cmaxdata for ODMT are dissimilar from the Tramadol results and aresupportive of bioequivalence between the Test Product (A) and ReferenceProduct (C) under fed conditions.

Table 11 summarizes the PK results for tramadol and O-desmethyltramadolobserved for Treatment A (viz., tramadol hydrochloride oral solution (50mg/10 mL) under fed conditions) and Treatment B (viz., tramadolhydrochloride oral solution (50 mg/10 mL) under fasted conditions). Withthe exception of Tmax (reported as a median value and minimum andmaximum ranges), the remaining PK values are reported as arithmeticmeans with corresponding standard deviations.

TABLE 11 Summary of PK Results for the Treatment A (fed) and Treatment B(fasted) Tramadol ODMT A B A B Parameters Mean ± SD Mean ± SD Mean ± SDMean ± SD Tmax (hr) # 2.0 (0.5-3.5) 1.9 (0.75-3.00) 3.50 (1.75-5.00)2.00 (0.75-3.50) Cmax (ng/mL) 146.22 ± 28.50 160.15 ± 34.10 41.35 ±11.53 45.66 ± 13.95 AUC0-t (hr * ng/mL) 1606.04 ± 574.38 1577.24 ±585.27 623.14 ± 167.54 635.30 ± 181.16 AUC0-inf (hr * ng/mL) 1635.90 ±594.44 1610.43 ± 616.17 635.05 ± 169.97 648.10 ± 181.52 t½ (hr)  7.33 ±1.19  7.68 ± 1.51 7.6 ± 1.1 8.0 ± 1.5 Kel (hr-1)  0.097 ± 0.015  0.093 ±0.017 0.094 ± 0.014 0.089 ± 0.015 # Median value for Tmax median with anassociated minimum and maximum range.

Least squares geometric means, ratio of means, and 90% geometricconfidence intervals were also determined for the Test Product (T) andReference Product (R), N=18, the results of which are presented in Table12.

TABLE 12 Least squares geometric means, ratio of means, and 90%geometric confidence intervals based on tramadol and ODMT for TreatmentA and Treatment B (Food Effect) PK-value A B Ratio, % 90% C.I. TramadolAUC0-t 1515.80 1484.1442 102.13 98.49-105.91 (hr * ng/mL) AUC0-inf1541.65 1510.5231 102.06 98.36-105.91 (hr * ng/mL) Cmax (ng/mL) 143.62156.7631 91.62 85.91-97.71  ODMT AUC0-t 601.08 607.18 99.00 94.86-103.31(hr * ng/mL) AUC0-inf 612.89 620.71 98.74 94.72-102.94 (hr * ng/mL) Cmax(ng/mL) 39.54 43.06 91.83 86.62-97.35 

As related to the AUC0-t for tramadol, the Test (A)/Test (B) ratio ofgeometric means was 102.13% and the 90% confidence interval for theratios of the ln-transformed means was found to be 98.49-105.91%. Andfor ODMT, the Test (A)/Test (B) ratio of geometric means was 99.00% andthe 90% confidence interval for the ratios of the ln-transformed meanswas found to be 94.86-103.31%.

As related to the AUC0-inf for tramadol, the Test (A)/Test (B) ratio ofgeometric means was 102.06% and the 90% confidence interval for theratios of the ln-transformed means was found to be 98.36-105.91%. Andfor ODMT, the Test (A)/Test (B) ratio of geometric means was 98.74% andthe 90% confidence interval for the ratios of the ln-transformed meanswas found to be 94.72-102.94%.

As related to Cmax for tramadol, the Test (A)/Test (B) ratio ofgeometric means was 91.62% and the 90% confidence interval for theratios of the ln-transformed means was found to be 85.91-97.71%. And forODMT, the Test (A)/Test (B) ratio of geometric means was 91.83% and the90% confidence interval for the ratios of the ln-transformed means wasfound to be 86.62-97.35%.

Based on the Food Effect results summarized in Table 12, it is concludedthat the Test Product (A) administered under fed condition isbioequivalent to the Test Product (B) administered in fasting condition.Accordingly, a food effect was not observed with the consumption of ahigh-fat, high calorie meal. The data of ODMT were comparable and alsodemonstrate no food effect with consumption of a high-fat, high caloriemeal.

The references cited herein are incorporated by reference in theirentirety to the extent necessary. In the event that there is adifference in meaning between the incorporated terms and the termsdisclosed herein and the terms of the related application, the meaningof the terms disclosed herein will control.

Alternative embodiments, examples, and modifications which would stillbe encompassed by the disclosure may be made by those skilled in theart, particularly in light of the foregoing teachings. Further, itshould be understood that the terminology used to describe thedisclosure is intended to be in the nature of words of descriptionrather than of limitation.

Those skilled in the art will also appreciate that various adaptationsand modifications of the preferred and alternative embodiments describedabove can be configured without departing from the scope and spirit ofthe disclosure. Therefore, it is to be understood that, within the scopeof the embodiments described herein, the disclosure may be practicedother than as specifically described herein.

The invention claimed is:
 1. An aqueous oral solution comprising: (a)from about 4.5 mg/mL to 5.5 mg/mL of tramadol hydrochloride as the soleactive ingredient; (b) propylene glycol; (c) from about 10% w/v to about30% w/v of glycerin, (d) water, and (e) a sufficient amount of a bufferto maintain the pH of the oral solution from about 4.5 to about 5.5. 2.The aqueous oral solution of claim 1, wherein the amount of propyleneglycol ranges from about 4% w/v to about 10% w/v.
 3. The aqueous oralsolution of claim 2, wherein the amount of propylene glycol ranges fromabout 5% w/v to about 7% w/v.
 4. The aqueous oral solution of claim 1further comprising sucralose.
 5. The aqueous oral solution of claim 1further comprising a flavoring agent.
 6. The aqueous oral solution ofclaim 1 further comprising sodium benzoate.
 7. The aqueous oral solutionof claim 6, wherein the amount of sodium benzoate ranges from about 0.1%w/v to about 1% w/v.
 8. The aqueous oral solution of claim 1, whereinthe aqueous oral solution is free or substantially free of polyethyleneglycol.
 9. The aqueous oral solution of claim 1, wherein the aqueousoral solution is free or substantially free of non-ionic surfactants andco-solvents.
 10. The aqueous oral solution of claim 1, wherein theaqueous oral solution is free or substantially free of sugars, parabens,castor oil, ethanol, polyethylene glycol, povidone, copovidone, sorbitanmonolaurate, mint oil, aniseed flavor, saccharin and salts thereof,sodium cyclamate, and polyoxyl 40 hydrogenated castor oil.
 11. Theaqueous oral solution of claim 1, wherein the solution exhibits anamount of tramadol hydrochloride of from about 0.45% w/v to about 0.55%w/v after storage at 25±2° C. and 40±5% relative humidity for 24 months.12. A method of treating pain in a subject in need thereof, whichcomprises administering to the subject an effective amount of theaqueous oral solution of claim 1.